Worldwide, head and neck squamous cell carcinoma (HNSCC) is the sixth most common neoplasm, and despite advances in therapy, long-term survival in HNSCC patients is poor. Primary surgery followed by chemoradiation, or primary chemoradiation, are the standard treatment options for patients with locally advanced HNSCC. Improvement in the therapy efficiency is being achieved by new derivatives of fluoropyrimidine, novel platinum compounds and targeted antibodies against the epidermal growth factor receptor. Novel targets are being developed involving integrins, cyclooxygenase, and intracellular signaling pathways. Therapeutic results are also reported for immunomodulatory drugs. Patient group stratification based on therapy relevant biomarkers might lead to improved efficiency for antibodies targeted against receptors or for kinase inhibitors.